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Pérusse, Louis

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Louis

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Université Laval. Département de kinésiologie

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  • PublicationAccès libre
    Methylation quantitative trait loci within the TOMM20 gene are associated with metabolic syndrome-related lipid alterations in severely obese subjects
    (BioMed Central Ltd., 2016-07-29) Toro Martin, Juan de; Guénard, Frédéric; Pérusse, Louis; Hould, Frédéric-Simon; Marceau, Picard; Vohl, Marie-Claude; Deshaies, Yves; Lebel, Stéfane; Tchernof, André
    Background : The TOMM20 gene was previously identified as differentially expressed and methylated between severely obese subjects with and without metabolic syndrome (MS). Since metabolic complications do not affect all obese patients to the same extent, the aim of this study was to identify methylation quantitative trait loci (meQTL) potentially associated with MS-related complications within the TOMM20 locus. Methods : Methylation profiling, SNP genotyping and meQTL association tests (general linear models) were performed in a population of 48 severely obese subjects. Genotyping was extended to a larger population of 1720 severely obese subjects with or without MS, where genotype- and diplotype-based association tests were assessed by logistic regression. In silico analyses were performed using TRAP. Results : Four SNPs were identified as significant meQTLs for the differentially methylated site cg16490124. Individuals carrying rare alleles of rs4567344 (A > G) (P = 4.9 × 10−2) and rs11301 (T > C) (P = 5.9 × 10−3) showed decreased methylation levels at this site, whereas those carrying rare alleles of rs4551650 (T > C) (P = 3.5 × 10−15) and rs17523127 (C > G) (P = 3.5 × 10−15) exhibited a significant increase in methylation. rs4567344 and rs11301 were associated with increased susceptibility to exhibit high plasma triglycerides (TG ≥ 1.69 mmol/L), while rare alleles of rs4551650 and rs17523127 were significantly more represented in the low plasma total-C group (total-C ≤ 6.2 mmol/L). Haplotype reconstruction with the four meQTLs (rs4567344, rs11301, rs4551650, rs17523127) led to the identification of ten different diplotypes, with H1/H2 (GCGG/ACGG) exhibiting a nearly absence of methylation at cg16490124, and showing the highest risk of elevated plasma TG levels [OR = 2.03 (1.59–3.59)], a novel association with elevated LDL-cholesterol [OR = 1.86 (1.06–3.27)] and the complete inversion of the protective effect on total-C levels [OR = 2.03 (1.59–3.59)], especially in men. In silico analyses revealed that rs17523127 overlapped the CpG site cg16490124 and encompassed the core binding sites of the transcription factors Egr 1, 2 and 3, located within the TOMM20 promoter region. Conclusion : This study demonstrates that TOMM20 SNPs associated with MS-related lipid alterations are meQTLs potentially exerting their action through a CpG methylation-dependent effect. The strength of the diplotype-based associations may denote a novel meQTL additive action and point to this locus as particularly relevant in the inter-individual variability observed in the metabolic profiles of obese subjects.
  • PublicationAccès libre
    Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome
    (Elsevier, 2017-02-01) Guénard, Frédéric; Biron, Simon; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Marceau, Simon (***WMS); Deshaies, Yves; Tchernof, André
    A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10−11) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)–binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels.
  • PublicationAccès libre
    The rare allele of DGKZ SNP rs10838599 is associated with variability in HDL-cholesterol levels among severely obese patients
    (Open Access Text Pvt. Ltd, 2016-05-12) Guénard, Frédéric; Pérusse, Louis; Hould, Frédéric-Simon; Deshaies, Yves; Marceau, Picard; Bégin, Stéphanie; Vohl, Marie-Claude; Lebel, Stéfane; Tchernof, André
    Introduction: Diacylglycerol kinase-zeta, one of the ten isoforms of DGKs expressed in mammals is an important enzyme of lipid metabolism. It catalyzes the interconversion of diacylglycerol and phosphatidic acid, two major second messengers. Its gene DGKZ has been previously identified as being overexpressed and undermethylated in visceral adipose tissue of patients with (MetS+) versus without (MetS-) the metabolic syndrome (MetS). Objective: The aim of this study was to investigate the associations between DGKZ gene polymorphisms (SNPs) and phenotypes related to MetS (BMI, waist girth, CRP, fasting glucose, lipid profile (triglycerides, total-cholesterol, LDL-cholesterol and HDL-cholesterol (HDL-C)), resting systolic and diastolic blood pressures). Methods: The study sample included 1752 severely obese participants who underwent bariatric surgery. Associations between the five selected tSNPs of DGKZ and features of the MetS were tested. The effects of these SNPs on DGKZ methylation and expression levels were tested in subgroups of 32 and 14 obese subjects, respectively. Correlations between methylation and expression levels were also computed. Results: Homozygotes for the rare allele of rs10838599 displayed higher plasma HDL-C concentrations compared to the other genotype groups (p=0.03). For gene methylation, only a trend with the cg05412031 CpG site (p=0.09) was found for the single significantly phenotype-associated SNP. There was no significant correlation between DGKZ methylation at cg05412031 and expression levels. Conclusion: These results suggest that DGKZ SNP rs10838599 modulates plasma HDL-C levels thereby its gene contributes to the inter-individual variability observed in the cardiometabolic risk profile of patients with severe obesity.
  • PublicationAccès libre
    DUSP1 gene polymorphisms are associated with obesity-related metabolic complications among severely obese patients and impact on gene methylation and expression
    (Hindawi Publishing Corporation, 2013-08-06) Guénard, Frédéric; Pérusse, Louis; Bouchard, Luigi; Hould, Frédéric-Simon; Marceau, Picard; Vohl, Marie-Claude; Deshaies, Yves; Lebel, Stéfane; Tchernof, André
    The DUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with versus without the metabolic syndrome. Objective. To test the association between DUSP1 polymorphisms, obesity-related metabolic complications, gene methylation, and expression levels in VAT. Methods. The DUSP1 locus and promoter region were sequenced in 25 individuals. SNPs were tested for association with obesity-related complications in a cohort of more than 1900 severely obese individuals. The impact of SNPs on methylation levels of 36 CpG sites and correlations between DNA methylation and gene expression levels in VAT were computed in a subset of 14 samples. Results. Heterozygotes for rs881150 had lower HDL-cholesterol levels (HDL-C; P = 0.01), and homozygotes for the minor allele of rs13184134 and rs7702178 had increased fasting glucose levels (P = 0.04 and 0.01, resp.). rs881150 was associated with methylation levels of CpG sites located ~1250 bp upstream the transcription start site. Methylation levels of 4 CpG sites were inversely correlated with DUSP1 gene expression. Conclusion. These results suggest that DUSP1 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels.
  • PublicationAccès libre
    Common sequence variants in CD163 gene are associated with plasma triglyceride and total cholesterol levels in severely obese individuals
    (Longdom Publishing SL, 2014-11-27) Guénard, Frédéric; Marianne, Cormier; Biron, Simon; Deshaies, Yves; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Marceau, Simon
    Objective: The CD163 glycoprotein is a member of the scavenger receptor cysteine-rich superfamily acting as an inflammatory modulator inducing anti-inflammatory pathways. Previous findings from our group identified this gene as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with vs. without the metabolic syndrome. The current study aimed to test the association between CD163 gene polymorphisms and obesity-related metabolic complications. Methods: Sequencing of the CD163 gene region was conducted in 25 severely obese individuals. Eleven tagging SNPs (tSNP) were selected and tested for association with obesity-related complications in nearly 1900 severely obese individuals. To further explore potential mechanisms underlying associations identified, the impact of tSNPs on methylation levels of 3 CpG sites (two promoter and one intronic) and gene expression levels were tested in a subset of 14 individuals. Results: Rare allele carriers for rs7980201 demonstrated lower fasting total cholesterol (total-C) levels (p=0.01) while rs4883263 rare allele carriers had increased total-C (p=0.04) and triglyceride (TG) levels (p=0.01). An association identified between rs7980201 SNP and methylation level of a promoter CpG site (p=0.04) suggested an impact on CD163 gene methylation in VAT, but such association was not reflected at gene expression level. Conclusion: The current study reports association of CD136 gene variations with fasting total-C and TG levels and suggests that CD163 SNPs could contribute to the inter-individual variability observed in obesity-related metabolic complications.
  • PublicationRestreint
    Contribution of genetic and metabolic syndrome to omental adipose tissue PAI-1 gene mRNA and plasma levels in obesity
    (Springer Nature, 2010-02-02) Pérusse, Louis; Mauriege, Pascale; Lebel, Stéfane; Hould, Frédéric-Simon; Marceau, Picard; Vohl, Marie-Claude; Bouchard, Luigi; Bergeron, Jean
    Background Plasminogen activator inhibitor type-1 (PAI-1) has already been associated with atherosclerosis; myocardial infarction; and cardiovascular disease risk factors such as obesity, insulin resistance, and dyslipidemia. However, factors regulating PAI-1 adipose tissue (AT) gene expression and plasma levels are not yet well defined. Aim This study aims to assess the contribution of PAI-1 omental AT mRNA levels and genetic and metabolic factors to variation in plasma PAI-1 concentrations. Methods Ninety-one non-diabetic premenopausal severely obese women (body mass index, BMI >35 kg/m2) undergoing bariatric surgery were phenotyped (fasting plasma glucose, lipid-lipoprotein, and PAI-1 levels) and genotyped for four PAI-1 polymorphisms. Omental AT PAI-1 mRNA levels were determined using real-time polymerase chain reaction. Stepwise regression analysis was used to identify independent PAI-1 AT mRNA and plasma level predictors. Results Among the variables included to the stepwise regression analysis, plasma high-density lipoprotein (HDL)-cholesterol (r = 0.38; p = 0.0004) and total cholesterol (r = 0.16; p = 0.0541) levels were the only two (out of 12) independent variables retained as predictive of PAI-1 omental AT mRNA levels, whereas BMI (r = 0.35; p = 0.0039), plasma HDL-cholesterol concentrations (r = −0.31; p = 0.0375), PAI-1 omental AT mRNA levels (r = 0.19; p = 0.0532) and PAI-1-844G/A (p = 0.0023), and rs6092 (p.A15T; p = 0.0358) polymorphisms contributed independently to plasma PAI-1 concentrations. Taken together, these variables explained 17.8% and 31.0% of the variability in PAI-1 AT mRNA and plasma levels, respectively. Conclusion These results suggest that PAI-1 polymorphisms contribute significantly to PAI-1 plasma levels but do not support the notion that omental AT is one of its major source.
  • PublicationRestreint
    A CpG-SNP located within the ARPC3 gene promoter is associated with hypertriglyceridemia in severely obese patients
    (S. Karger AG, 2016-04-08) Guénard, Frédéric; Biron, Simon; Toro Martin, Juan de; Deshaies, Yves; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Tchernof, André; Marceau, Simon
    Aims: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients. Methods: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men. Results: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02). Conclusions: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism.
  • PublicationRestreint
    The peroxisome proliferator-activated receptor α L162V mutation is associated with reduced adiposity
    (North American Association for the Study of Obesity, 2012-09-06) Bouchard, Claude; Pérusse, Louis; Bossé, Yohan; Vohl, Marie-Claude; Després, Jean-Pierre
    Objective: To determine the contribution of the peroxisome proliferator-activated receptor α (PPARα) L162V mutation to the variation of several indexes of body fatness obtained from healthy adults who participated in the Quebec Family Study. Research Methods and Procedures: The PPARα L162V mutation was determined by a mismatch polymerase chain reaction method. Adiposity phenotypes were obtained by standardized anthropometric measurements, underwater weighing technique, and computed tomography. Results: For all adiposity phenotypes, subjects carrying the V162 allele had lower values compared with L162 homozygotes (HMZs) [BMI (kg/m2): 27.8 ± 7.6 vs. 26.0 ± 5.6, p < 0.05; percentage body fat: 28.5 ± 10.7 vs. 25.7 ± 10.1, p < 0.05; waist circumference (cm): 89.0 ± 18.1 vs. 85.7 ± 15.8, p = 0.07; total computed tomography abdominal fat areas (cm2): 406 ± 221 vs. 359 ± 192, p = 0.15; means ± SD for L162 HMZs vs. V162 carriers, respectively]. Differences in cross-sectional abdominal adipose tissue areas and waist circumference were abolished after adjustment for total body fat mass. Similar trends were observed when results were analyzed by gender, although associations seemed stronger in women. The odds ratio of having a BMI above 30 kg/m2 reached 1.77 (1.02; 3.07, 95% confidence intervals) for L162 HMZs. This risk could be considered marginal on an individual basis, but because 85% of the subjects are affected by this small risk, the impact on the population is important. Discussion: The PPARα V162 allele is associated with reduced adiposity and has a substantial population-attributable risk.
  • PublicationRestreint
    LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes.
    (Springer Nature, 2012-07-02) Biron, Simon; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Bélisle, Alexandre; Turcot, Valérie; Marceau, Simon; Vohl, Marie-Claude; Deshaies, Yves; Tchernof, André
    Background: Epigenetic mechanisms may be involved in the regulation of genes found to be differentially expressed in the visceral adipose tissue (VAT) of severely obese subjects with (MetS+) versus without (MetS-) metabolic syndrome (MetS). Long interspersed nuclear element 1 (LINE-1) elements DNA methylation levels (% meth) in blood, a marker of global DNA methylation, have recently been associated with fasting glucose, blood lipids, heart diseases and stroke. Aim: To test whether LINE-1%meth levels in VAT are associated with MetS phenotypes and whether they can predict MetS risk in severely obese individuals. Methods: DNA was extracted from VAT of 34 men (MetS-: n = 14, MetS+: n = 20) and 152 premenopausal women (MetS-: n = 84; MetS+: n = 68) undergoing biliopancreatic diversion for the treatment of obesity. LINE-1%meth levels were assessed by pyrosequencing of sodium bisulfite-treated DNA. Results: The mean LINE-1%meth in VAT was of 75.8% (SD = 3.0%). Multiple linear regression analyses revealed that LINE-1%meth was negatively associated with fasting glucose levels (β = -0.04; P = 0.03), diastolic blood pressure (β = -0.65; P = 0.03) and MetS status (β = -0.04; P = 0.004) after adjustments for the effects of age, sex, waist circumference (except for MetS status) and smoking. While dividing subjects into quartiles based on their LINE-1%meth (Q1 to Q4: lower %meth to higher %meth levels), greater risk were observed in the first (Q1: odds ratio (OR) = 4.37, P = 0.004) and the second (Q2: OR = 4.76, P = 0.002) quartiles compared to Q4 (1.00) when adjusting for age, sex and smoking. Conclusions: These results suggest that lower global DNA methylation, assessed by LINE-1 repetitive elements methylation analysis, would be associated with a greater risk for MetS in the presence of obesity.
  • PublicationAccès libre
    Comparison of the dipeptidyl peptidase-4 gene methylation levels between severely obese subjects with and without the metabolic syndrome
    (BioMed Central Ltd., 2013-02-04) Pérusse, Louis; Turcot, Valérie; Deshaies, Yves; Hould, Frédéric-Simon; Marceau, Picard; Belisle, Alexandre; Vohl, Marie-Claude; Tchernof, André; Lebel, Stéfane
    Background : The dipeptidyl peptidase-4 (DPP4) enzyme is a novel adipokine potentially involved in the development of the metabolic syndrome (MetS). Previous observations demonstrated higher visceral adipose tissue (VAT) DPP4 gene expression in non-diabetic severely obese men with (MetS+) vs. without (MetS−) MetS. DPP4 mRNA abundance in VAT correlated also with CpG site methylation levels (%Meth) localized within and near its exon 2 (CpG94 to CpG102) in non-diabetic severely obese women, regardless of their MetS status. The actual study tested whether DPP4 %Meth levels in VAT are different between MetS− and MetS+ non-diabetic severely obese subjects, whether variable metabolic and plasma lipid profiles are observed between DPP4 %Meth quartiles, and whether correlation exists in DPP4 %Meth levels between VAT and white blood cells (WBCs). Methods : DNA was extracted from the VAT of 26 men (MetS−: n=12, MetS+: n=14) and 79 women (MetS−: n=60; MetS+: n=19), as well as from WBCs in a sub-sample of 17 women (MetS−: n=9; MetS+: n=8). The %Meth levels of CpG94 to CpG102 were assessed by pyrosequencing of sodium bisulfite-treated DNA. ANOVA analyses were used to compare the %Meth of CpGs between MetS− and MetS+ groups, and to compare the metabolic phenotype and plasma lipid levels between methylation quartiles. Pearson correlation coefficient analyses were computed to test the relationship between VAT and WBCs CpG94-102 %Meth levels. Results : No difference was observed in CpG94-102 %Meth levels between MetS− and MetS+ subjects in VAT (P=0.67), but individuals categorized into CpG94-102 %Meth quartiles had variable plasma total-cholesterol concentrations (P=0.04). The %Meth levels of four CpGs in VAT were significantly correlated with those observed in WBCs (r=0.55−0.59, P≤0.03). Conclusions : This study demonstrated that %Meth of CpGs localized within and near the exon 2 of the DPP4 gene in VAT are not associated with MetS status. The actual study also revealed an association between the %Meth of this locus with plasma total-cholesterol in severe obesity, which suggests a link between the DPP4 gene and plasma lipid levels.